Purpose: Purpose: 1. To identify the receptors on malaria parasites for red cell invasion and on infected red cells for adhesion to endothelium and to placenta. 2. To identify the red cell receptors for each parasite ligand. 3.To identify the basis of the dichotomy between parasites that bind placenta and parasites that bind to endothelium. 4. Test a region on the variant antigen for inducing protection against P. falciparum in Aotus monkeys and for overcoming variation. Accomplishments during the year: 1. Five mutations were identified worldwide in one of the P. falciparum parasite receptor. Each mutation binds to a different receptor on the red cell. The parasite receptor for other members of this family are shown to bind red cells 2. The domain on the variant antigen for binding chondroitin sulfate A in placenta has been identified. As the binding of infected red cells in placenta is associated with fetal and newborn mortality, blocking this with a vaccine may reduce disease. Antibodies to this domain appear to be cross- reactive to parasites from around the world. We are working on this domain as a vaccine candidate. We have identified the basis of the dichotomous binding to CD36 in placenta or CIDR1 on endothelium. The minimal parasite domain has been synthesized and used as an immunogen. 3. The first vaccine trial against one of the domain of the variant antigen (CIDR1) on the red cell surface for binding endothelium has been used in a vaccine in Aotus monkeys that protected against the homologous strain but not the heterologous one. We are using a strategy of gene shuffling with Maxygen to overcome the problem of variability.